Early life stress impairs DG formation by down regulating Autotaxin

描述（由申请方提供）：自分泌运动因子（ATX）是一种分泌型溶血磷脂酶，在胚胎发育期间对神经干细胞（NSC）的正常增殖、迁移和存活至关重要。ATX的缺失是胚胎致死的，这解释了缺乏关于其在围产期（出生后1-21天）期间支持NSC增殖的作用的信息。在这里，我们表明，ATX在海马（HP）的表达在围产期达到峰值，并显着下降时，小鼠幼崽暴露于慢性或急性应激在此期间。我们还提出了初步的数据，21日龄的幼崽，是杂合子的ATX基因有减少的NSC在齿状回（DG）的增殖和减少颗粒细胞层（GCL）的体积。基于这些初步数据，我们假设发育中的HP中的ATX表达对于正常DG发育是必不可少的（目的1），暴露于早期生活应激（ELS）的幼仔恢复正常水平的ATX将阻断ELS对DG发育的抑制作用（目的2），发育中的HP中的ATX表达受皮质酮水平的快速调节（目的3）。如果得到证实，这项工作将对以前的工作作出三个重要贡献。首先，它将首次证明， DG的形成，在围产期，需要高表达水平的ATX。其次，它将表明血浆中的皮质酮水平严格调节发育中HP的ATX水平。第三，它将提供一个新的分子机制来解释如何暴露于压力，在围产期，影响DG的发展。我们预测ATX在人类DG发育中起着类似的作用，这项工作将确定一个关键途径，通过该途径，生命早期的虐待和忽视会导致成年人HP的长期功能障碍。.

DESCRIPTION (provided by applicant): Autotaxin (ATX) is a secreted lysophospholipase that is essential for normal proliferation, migration, and survival of neural stem cells (NSC) during embryonic development. Deletion of ATX is embryonic lethal explaining the lack of information regarding its role in supporting NSC proliferation during the perinatal period (postnatal days 1-21). Here we show that expression of ATX in the hippocampus (HP) peaks during the perinatal period and is dramatically decreased when mice pups are exposed to chronic or acute stress during this period. We also present preliminary data that 21-day old pups that are heterozygous for the ATX gene have reduced NSC proliferation in the dentate gyrus (DG) and a decrease in granule cell layer (GCL) volume. Based on these preliminary data we hypothesize that ATX expression in the developing HP is essential for normal DG development (aim 1), that restoring normal levels of ATX to pups exposed to early life stress (ELS) will block the inhibitory effect that ELS has on DG development (aim 2), and that ATX expression in the developing HP is rapidly regulated by corticosterone levels (aim 3). If confirmed, this work will make three important contributions to previous work. First, it will demonstrate for the first time that normal DG formation, during the perinatal period, requires high expression levels of ATX. Second, it will show that corticosterone levels in the plasma tightly regulate ATX levels in the developing HP. Third, it will provide a novel molecular mechanism to explain how exposure to stress, during the perinatal period, affects DG development. We predict that ATX plays a similar role in DG development in humans, and that this work will identify a critical pathway by which abuse and neglect early in life cause long-term dysfunction in the HP of adult humans. .